Aminoglycoside antibiotics (AGAs) are clinically important drugs effective against a broad range of microorganisms. The clinical use of AGAs is restricted by toxicity (irreversible ototoxicity and reversible nephrotoxicity) and by the resistance of pathogens to AGAs. Common to 2-deoxystreptamine derived AGAs is a pseudodisaccharide core of the neamine type. It is composed of 2-deoxystreptamine (ring II) glycosidically linked to an aminodeoxyglucopyranose (ring I). Additional glycosyl moieties are attached to the hydroxy groups of the 2-deoxystreptamine moiety to give rise to a variety of compounds, categorized as 4,5- or 4,6-substituted deoxystreptamine-derived aminoglycosides, such as paromomycin (1a) and kanamycin A (1b).

AGAs affect the fidelity of protein synthesis through binding to specific sites of the ribosomal RNA (rRNA) (Magnet et al., Chem. Rev. 2005, 105, 477; Jana et al., Appl. Microbiol. Biotechnol. 2006, 70, 140; Vicens et al., Chembiochem 2003, 4, 1018; Ogle et al., Trends Biochem Sci 2003, 28, 259). In spite of decades of use of ribosomal drugs, the structural features governing selectivity, i.e. the discrimination between prokaryotic and eukaryotic ribosomes, and the toxicity of these compounds are still not fully understood. Genetic studies (Hobble et al., Antimicrob. Agents Chemother. 2006, 50, 1489; Hobbie et al., C. Antimicrob. Agents Chemother. 2005, 49, 5112; Boettger et al., EMBO reports 2001, 2, 318) and crystal structures of AGAs complexed with ribosomal subunits (Carter et al. Nature 2000, 407, 340; Francois et al. Nucleic Acids Res 2005, 33, 5677; and above mentioned references) have contributed to understanding the interactions of AGAs with the rRNA target.
The above-mentioned studies have shown that the aminodeoxyglucopyranosyl ring I of 2-deoxystreptamine-derived AGAs binds to the rRNA in the same way regardless of whether the 2-deoxystreptamine is 4,5- or 4,6-disubstituted. According to the crystal structures of several AGAs, ring I intercalates into the bulge formed by A1408, A1492 and A1493, and the base pair C1409-G1491. Ring I stacks upon G1491 and forms a pseudo base pair with A1408 characterized by H-bonds from C(6′)-OH to N(1) of A1408, and from C(5′)-OH to N(6) of A1408. Additionally, ring I shows two non-specific interactions with the phosphate groups of the two flipped-out adenines 1492 and 1493: C(3′)-OH forms an hydrogen bond with O2P of A1492, and C(4′)-OH forms a hydrogen bond with O2P of A1493.
Neamine-based derivatives are currently under investigation for reducing bacterial) aminoglyoside resistance and for use as anti-HIV agents.
U.S. patent application 2006/0211634 A1 teaches the use of neamine-based compounds for inhibiting aminoglycoside-6″-N-acetyltransferases capable of reversing or inhibiting bacterial resistance to aminoglycoside antibiotics. These compounds are characterized by large substituents on the 6′position such as Coenzyme A. They are not suggested for use as antibiotics.
WO 2005/060573 teaches compositions for modulating the activity of a nucleic acid molecule comprising a peptide nucleic acid moiety conjugated to a neamine moiety. The document does not disclose antibiotic activity for these compositions.
Feng et al. (Angew. Chem. Int. Ed. 2005, 44, 6859-6862) discloses the regio- and chemoselective 6′-N-derivatisation of neamine-based aminoglycosides with coenzyme A resulting in bisubstrate inhibitors as probes for studying aminoglycoside 6′-N-acetyltransferases (AAC(6′) inhibitors). The same authors (Feng et al., J. Med. Chem. 2006, 4, 5273-5281) describe second generation AAC(6′) inhibitors based on neamine having long polypeptidic substituents in the 6′ position.
Riguet et al. (Tetrahedron 60, 2004: 8053-8064) teach a route for preparing neamine-based derivatives with heterocyclic substituents bound by linker units for targeting HIV1 TAR RNA. Later the same authors teach (Bioorganic & Medicinal Chemistry Letters 15 (2005) 4651-4655) neamine-based dimers and trimers for targeting HIV-1 TAR RNA.
Due to their high toxicity and significant levels of antibiotic resistance neamine-based aminoglycosides are presently of limited use.
The object underlying the present invention is to provide novel and improved antimicrobial compounds that are not modified by common microbial resistance determinants and that target microbial, in particular bacterial 16S ribosomal RNA, i.e. the compounds do not target at all or target to a substantially less degree eukaryotic cytosolic and/or mitochiondrial ribosomes.